Patients with malignat myeloproliferative disease often have bleeding or thrombosis and laboratory evidence of abnoraml platelet function. Our preliminary studies have demonstrated striking ultrastructural changes of platelets and small circulating megakaryocytes in those patients. We propose a combined functional and electron microscopic study and biochemical analysis of the abnormal platelets and megakaryocytes. Ultimately we seek a definition of the platelet and megakaryocytic defect at a subcellular level. We expect to gain clinically useful information on the platelet hemostatic abnormalities in the myeloproliferative diseases. By utilizing the pathologic platelet line as a model we expect to add to the knowledge to normal platelet physiology and megakaryocyte-platelet developement. We will continue our studies of myeloproliferative disease to: 1) Further define the ultrastructural abnormalities of the platelets and megakaryocytes; 2) Establish that the abnormalities of the platelets reflect a primary defect of the structure and development of the megakaryocyte by simulataneous study of the peripheral blood and bone marrow by electron microscopy, histochemistry and microspectrophotometry; 3) Define the ultrastructural changes of these abnormal platelets and circulating megakaryocytes during in vitro aggregation; 4) Elucidate some of the biochemical defects by determination of the platelets contet of serotonin, adenine nucleotides and platelets factors 3 and 4 in whole cells and in subcellular fractions. The platelets will be separated by differential centrifugation or density gradient to analyze and compare the changes in the various cell populations. Whenever feasible serial studies will be performed to evaluate changes occurring as a result of natural evolution of the disease or as a result of therapy. We hope that the results of our investigation will lead to more effective management of the hemostatic complications of patients with myeloproliferative diseases. o